Human minibrain homologue (MNBH/DYRK1): Characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome

The human homologue (MNBH/DYRK1) of the Drosophila minibrain gene maps to h uman chromosome 21 within the Down syndrome (DS) critical region and is wit hin the region minimally deleted in chromosome 21-linked microcephaly. As a first step in gaining insight into the role that MNBH may have in human ne urogenesis, and as a lead-up to the development of mouse models for MNBH ov erexpression, we have characterized the gene at the molecular level. We des cribe here the MNBH full-length transcript, alternative splicing, expressio n profile, and genomic organization. The full-length cDNA of MNBH is 5.2 kb and is composed of 17 exons spanning 150 kb, between markers D21S335 and D 21S337. Transcripts MNBHa and MNBHb arise from the use of different first e xons in the 5'-UTR and are differentially expressed. MNBHa is expressed ubi quitiously in a broad spectrum of tissues and is apparently under the contr ol of a CpG; island. MNBHb is expressed only in heart and skeletal muscle a nd is apparently under the control of a TATA-like box. Four alternative spl icing events affecting the C-terminus of the protein yield at least four is oforms of MNBH (MNBH-iso1, MNBH-iso2, MNBH-iso3, and MNBH-iso4). A PEST seq uence, potentially involved in the rapid degradation of the protein, is pre sent in all the isoforms. A histidine repeat and a serine/threonine domain are present only in the largest form of the protein (MNBH-iso1). MNBH was o verexpressed 1.5-fold in DS brains and Dyrk1 about 2.1-fold in the brains o f the Ts65Dn mice. The information provided here should be valuable for MNB H mutation studies and aid in the development of DS animal models. (C) 1999 Academic Press.